Aging is a degenerative biological process that affects multiple organs including kidneys. The kidney function declines in the aged population. The aging-related kidney damage is an important aging process that determines the lifespan. The incidence of kidney damage increases in the aged population. For instance, the prevalence of chronic kidney disease (CKD) is higher in the aged than in the young population. Arterial stiffening, hypertension and angiogenesis are associated with CKD. CKD eventually results in multiple organ dysfunctions leading to heart failure and stroke. However, the etiology and pathogenesis of aging-related kidney damage are poorly understood. Klotho is a recently-discovered anti-aging gene. In humans, the klotho level declines in the aged population. Mutation of klotho gene shortens the lifespan while overexpression of klotho gene extends lifespan in mice. Klotho is predominately expressed in the kidney. CKD is associated with disrupted expression of renal klotho. Our new exciting preliminary data showed kidney-specific knockout of klotho gene caused interstitial fibrosis and glomerulosclerosis and impaired renal function in mice. The preliminary study also demonstrated that renal klotho expression was markedly decreased in the aging kidneys. The overall objective of this application is to determine if klotho plays a role in the maintenance of normal kidney structure and function and if klotho deficiency is involved in the pathogenesis of aging-related kidney damage (interstitial fibrosis, glomerulosclerosis, and impaired kidney function). This objective will be achieved by pursuing two coherent specific aims using a combination of several novel approaches including conditional gene knockout and in vivo tubule cell- specific and podocyte-specific gene delivery. The two specific aims are: (1) Determine if klotho deficiency causes kidney damage and related cellular and molecular mechanisms. (2) Determine if in vivo delivery of klotho gene attenuates the aging-related impairment in kidney structure and function in F344 rats. These studies will demonstrate an important role of klotho in the maintenance of normal kidney structure and function. The results will reveal novel molecular pathways that mediate the pathogenesis of aging-related kidney damage. Completion of this project may offer new insights into therapeutic strategies for aging-related kidney damage.